Measurement of insulin, C-peptide, glucagon, and somatostatin are central to epidemiological and metabolic studies which address the role of islet cell function and regulation and insulin resistance in the development and maintenance of obesity and diabetes in the Pima population. In vivo insulin catabolism, assessed by the hyperinsulinemic glucose clamp technique or as fractional extraction of endogenously secreted insulin, was elevated in obese diabetic patients compared to obese nondiabetic controls. The increased insulin clearance rate may contribute to the post-challenge hypoinsulinemia observed in diabetic patients. In addition, the cross-sectional differences and longitudinal changes in serum insulin levels in the Pima population were examined in relationship to diabetes and obesity.